This invention relates to a process for the large scale preparation of 3-cyano-6-alkoxy-7-nitro-4-quinolones, which are intermediates for the preparation of protein tyrosine kinase (PTK) inhibitors useful in the treatment of cancer.
The two most frequently used synthetic methods for the preparation of 3-cyano-4-quinolones or 3-carboalkyloxyquinolones are intramolecular Friedel-Crafts reactions and electrocyclic ring closures of N-(2-carboxyvinyl)-aniline derivatives. Friedel-Crafts conditions work well for electron rich anilines, moderately for unsubstituted anilines, and poorly or not at all for electron-deficient anilines and are especially not useful for large scale preparation of 3-cyano-4-quinolones utilizing electron deficient anilines. The electron withdrawing groups of the aniline reduce the nucleophilicity of the aromatic ring to the point that side reactions compete with, if not dominate, the desired intramolecular condensation. Thermal conditions for electrocyclic ring closures of N-(2-carboxyvinyl)-aniline derivatives typically require temperatures in excess of 240° C. However, the construction of 3-cyano-4-quinolones has been achieved by electrocyclic ring closure reactions of N-(2-carboxyvinyl) aniline derivatives by heating to 260° C. in diphenyl ether (U.S. Pat. No. 6,002,008; WO 98/43960). In particular, there are several deficiencies associated with electrocyclic ring closures for preparing quantities of material on a process scale. Typically, reactions are run at high dilution (66:1) resulting in an inefficient large-scale process due to low throughput. Further, thermal decomposition of either the final product and/or the starting material compromises the purity of the final product as a result of the high temperature reaction conditions. Additionally, equipment necessary to perform high temperature reactions safely on larger scale is expensive and not available in a typical laboratory or plant environment.
The production of 3-cyano-4-quinolones by electrocyclic ring closure suffers from all of the problems mentioned above, especially thermal decomposition of the desired final product or the starting material. For example, it is known that 7-ethoxy-4-hydroxy-6-nitroquinoline-3-carbonitrile decomposes at 240° C. while the minimum temperature required for cyclization is 256° C.
Thus, there is a need in the art for a process that addresses and preferably overcomes the high temperature cyclization, which results in thermal decomposition.
The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed to limit in any way the invention set forth in the claims that follow thereafter.